MDR1 Gene Mutation
How relevant is it to your dog and its veterinary treatment?
MDR1 - the Multiple Drug Resistance 1 gene, is a very important gene to humans, dogs, cats and other species. It produces a protein called P-glycoprotein (Pgp), and its role is to protect the cells of the body from toxic substances and, if necessary, to clear the body of toxins that are produced by certain drugs. Pgp also prevents these toxins from crossing the blood-brain-barrier (BBB). If P-glycoprotein isn’t present or is insufficient, the body is unable to excrete the drug, and toxins will build up within the brain resulting in neurological effects ranging from tremors through to seizures, coma and possibly death. This effect was first discovered in the 1980’s, by chance, in laboratory mice.
This could be why some dogs respond well to certain drugs and others fail to respond, and in fact, may suffer severe adverse reactions as a result. The MDR1 gene is an essential tool when it comes to excreting toxins from the body and this discovery explains how the response to certain drugs is often determined by the individual’s genetic make-up.
Which breeds are affected?
Australian Shepherds, Border Collies, Collies (Rough & Smooth), English Shepherds, German Shepherds, Long Haired Whippets, McNabbs, Miniature American (Australian) Shepherds, Mix-breeds, Old English Sheepdog, Shetland Sheepdog, Silken Windhounds
(Ref: http://www.ashgi.org/home-page/genetics-info/faq/mdr1-faqs)
It is now known that collie and herding breeds are more predisposed to having this gene mutation and this will affect how certain drugs are absorbed, but more importantly how efficiently (or inefficiently) they are excreted from the body. Dogs with the MDR1 gene mutation are unable to provide the necessary blood-brain-barrier protection that prevents the build-up of toxins from certain drugs within the brain, and the results of this can sometimes be devastating.
Some non-herding breeds of dog may still have this mutation from relative’s way back in their pedigree. Apparently the frequency of white dogs affected is greater than dogs of other colours (Ref: Adverse Drug Reaction in Herding Breeds of Dog). This gene mutation is the scientific explanation for the old adage “White feet – don’t treat” that appeared in the late 1980’s and early 90’s when Ivermectin treatment was given to dogs for heartworm prevention, but clearly many other breeds are at risk and also, there are other drugs can be problematic for dogs with this mutation.
The purpose of this article is to alert dog owners to the drugs that may have the potential to cause a serious adverse reaction in dogs with the MDR1 gene mutation, and to encourage every owner to test their dog for this gene mutation.
If the MDR1 gene result is negative for the mutation, rest assured your dog will not be affected by any of the listed drugs; but if the result is positive, meaning that the dog has the MDR1 gene mutation, then it is at risk and your vet should clearly mark a warning ‘Positive for MDR1 Gene Mutation’, on your dog’s veterinary notes.
It is a simple autosomal recessive condition so dogs are NN (normal), PN (carriers mildly affected) or PP (affected) – although penetrance is somewhat variable even among PP dogs. (http://www.genomia.cz/en/test/mdr1)
Dogs with a single copy of the MDR1 gene mutation can react to certain drugs causing mild to moderate neurological signs, but two copies of this gene mutation can lead to toxicity that may result in very serious consequences.
An adverse reaction in a dog with MDR1 gene mutation can be caused simply by using a commonly used, regular wormer or a parasitic prevention; or a sedative; or treatment for diarrhoea. The reason why drugs like Ivermectin are so powerful against parasites is because they are designed to damage their nervous system and cause paralysis, and this is without doubt a very effective form of parasitic control for dogs with a normal MDR1 Gene because the drug is prevented from crossing the blood-brain- barrier (BBB). Dogs with the MDR1 gene mutation however, the story is very different because they do not have the protection of P-glycoprotein and the BBB, and therefore their brain cells are more susceptible to potentially catastrophic toxic effects.
There are newer drugs on the market that might be more appropriate to use but these should still be considered with caution in a dog known to have the MDR1 gene mutation.
Having a test for the MDR1 gene mutation is very important, especially if your dog needs treatment with one or more of the following drugs:
“Drugs that have been documented to cause problems in dogs with the MDR1 mutation include:
Ivermectin (antiparasitic agent)
Selamectin, milbemycin and moxidectin (antiparasitic agents)
Loperamide (Imodium, antidiarrheal agent)
Acepromazine (tranquiliser and pre-anaesthetic agent)
Butorphanol (analgesic and pre-anaesthetic agent)
Chemotherapy agents (Vincristine, Vinblastine, Doxorubicin, Paclitaxel)”
“Drugs that are known to be pumped out of the brain by the protein that the MDR1 gene is responsible for producing but appear to be safely tolerated by dogs with the MDR1 mutation
Cyclosporin (immunosuppressive agent)
Digoxin (Cardiac drug)
Doxycycline (antibacterial drug)”
Ref: Washington State University. http://vcpl.vetmed.wsu.edu/problem-drugs
The above is an excellent reference. Please visit their website for much more information about drugs and the MDR1 gene mutation.
Dogs with this gene mutation will react to certain drugs, but to what degree depends on the dosage.
My Bearded Collie, Roly had demodex, a very nasty parasite that more often than not is kept under control by the dog’s own immune system. Demodex took hold after Roly was treated with immunosuppressive doses of prednisolone (a steroid) for an autoimmune disease. His immune system was suppressed and therefore the mite was allowed to become active. This is not uncommon in dogs whose immune system is significantly suppressed. It can also occur in very young dogs or older dogs with a compromised immune system.
I tried everything available to treat Roly for the demodex infestation without success, everything that is, except Ivermectin. I was aware of the sensitivity and possible adverse reaction to this drug in collie breeds and this is why I had resisted to use it until I had no choice because the lesions caused by the mites had become extreme. At this time there were no DNA tests available to identify this gene or mutation. I expressed my concern to the vet and we agreed to use one quarter of the pipette to start with and if Roly didn’t show a reaction then three days later I would administer another quarter of the pipette. All went well with the first dose, and as planned three days later I gave him another quarter of the pipette – and the effect shortly afterwards was devastating. His clinical signs were unmistakable. He had no control of his limbs. They were uncoordinated and just buckled beneath him. His pupils were dilated and he was trembling and shaking. How Roly would have reacted if I had given him the full dose doesn’t bear thinking about.
“In 1985 it was discovered that only 1/200th dose of Ivermectin could be fatal to collies” The MDR1 gene, its story and its significance in collies by Niell Taylor BVM&S, MRCVS GPCert(SAM) http://www.ovg.co.uk/MDR1.html
Roly slowly recovered from the effects of the drug but, unfortunately, we never got control of the demodex. Having experience this adverse drug reaction first-hand, I can fully appreciate why knowing the MDR1 gene status of your dog is so valuable. Ivermectin is only one drug on the list of many that might cause such a reaction. I didn’t know Roly’s status, and Bearded Collies are not known for this gene mutation, but I can confidently assume that he had the MDR1 gene mutation because:
“If your dog has already reacted to one of the listed drugs, it has the mutation” (http://www.ashgi.org/home-page/genetics-info/faq/mdr1-faqs MDR1 FAQs Rev Mar 2013)
and there was no doubt about Roly’s reaction.
I want to highlight one other drug that can be used in the treatment of an autoimmune disease that destroys the blood platelets. This drug is Vincristine. Vincristine is not used very often but it has the reputation of being able to rapidly increase blood platelets, and if a dog has immune mediated thrombocytopenia (IMTP) this drug could save its life. However, Vincristine is one of the drugs on the list that is more likely to cause an adverse reaction if the dog has MDR1 gene mutation therefore one has to consider if a gene test should be performed, especially if the dog is of a susceptible breed, before Vincristine is given. The correct drug regimen is crucial to the outcome of a dog with an autoimmune disease, and the wrong choice of drugs could have dire consequences and should be avoided at all times.
The DNA test for MDR1 gene mutation is either a simple cheek swab or blood sample. The test is extremely accurate and well worth having done.
To find out more about the MDR1 gene mutation and its implications, please check out the references provided in this article.
Jo Tucker
Please Note: All information is provided for your assistance and reference purposes only and is not meant in any way to substitute advice or treatment from your veterinary surgeon
For a list of laboratories that provide DNA tests:
Other references:
http://www.laboklin.co.uk/laboklin/showGeneticTest.jsp?testID=8032
Adverse Drug Reactions in Herding-Breed Dogs: The Role of P-Glycoprotein By Katerina L Mealey DVM, PhD, DACVIM, DACVCP
https://petxtreme.wordpress.com/2011/05/29/adverse-drug-reactions-in-herding-breed-dogs/